Authors

Date of Completion

Embargo Period

Keywords

Major Advisor

Dennis L. Wright

Associate Advisor

Amy Anderson

Associate Advisor

Mark Peczuh

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The presence of a heterocyclic moiety can be observed in many of today’s bioactive natural products. One of the most commonly observed is furan, an aromatic five-membered ring containing an oxygen atom. Furan is a simple compound, yet versatile enough to be used as a synthetic synthon leading to complex structures such as the antioxidant Phelligridin G and the antibacterial agent Platensimycin. In the former, it is spiro-fused to the five-membered carbocycle of the 6-5-5 tricyclic domain while in the latter it makes up the ether-bridged cycloadduct of the hydrophobic cage. Conventionally, furan can undergo cycloadditions in the presence of reactive dienophiles via the Diels-Alder reaction to form oxabicyclic synthons.

A strategy for the synthesis of the embedded spirocyclic core of phelligridin G from a 2-phenylfuran system was developed. Finding a suitable dienophile compatible with this biphenyl ring was a daunting task; however, we successfully obtained the oxabicyclo[2.2.1]heptadiene intermediate upon surveying a plethora of available dienophiles. Exposure of the strained ring system to the Grubbs’ 2nd generation ruthenium-based catalyst facilitated a domino ring-opening metathesis/ring-closing metathesis (ROM/RCM) to give a spiroannulated furan. Further evaluation showed the highly reactive tetrachlorocyclopropene was a compatible dienophile leading to the formation of spiro-fused pyran ring structures through a related metathesis approach.

Recently, we have developed a novel and expedient route towards the tetracyclic caged domain of platensimycin using an oxabicyclo[3.2.1]octadiene building block. Within our methodology a late-stage intermediate has been established from the [4+3] cycloaddition of a substituted furan with tetrabromocyclopropene along with an intramolecular γ–alkylation to form the seco-cage of this hydrophobic region. It has been postulated that structural modifications could help improve its poor pharmacokinetic profile while retaining potent bioactivity. Utilizing this furan-based route has led to the synthesis of several novel analogues that will be evaluated for their antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). We have assembled a unique derivative in which the cyclohexanone moiety has been replaced with the more constricted cyclopentanone ring. A second series of analogues synthesized have the C-ring completely removed from the caged domain and manipulation of the ketone functionality was evaluated.